Direct control of CAR T cells through small molecule-regulated antibodies

Spencer Park, Edward Pascua, Kevin C. Lindquist, Christopher Kimberlin, Xiaodi Deng, Yvonne S. L. Mak, Zea Melton, Theodore O. Johnson, Regina Lin, Bijan Boldajipour, Robert T. Abraham, Jaume Pons, Barbra Johnson Sasu, Thomas J. Van Blarcom () and Javier Chaparro-Riggers ()
Additional contact information
Spencer Park: Pfizer
Edward Pascua: Pfizer
Kevin C. Lindquist: Pfizer
Christopher Kimberlin: Pfizer
Xiaodi Deng: Pfizer
Yvonne S. L. Mak: Pfizer
Zea Melton: Pfizer
Theodore O. Johnson: Pfizer
Regina Lin: Pfizer
Bijan Boldajipour: Pfizer
Robert T. Abraham: Pfizer
Jaume Pons: Pfizer
Barbra Johnson Sasu: Pfizer
Thomas J. Van Blarcom: Pfizer
Javier Chaparro-Riggers: Pfizer

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Antibody-based therapeutics have experienced a rapid growth in recent years and are now utilized in various modalities spanning from conventional antibodies, antibody-drug conjugates, bispecific antibodies to chimeric antigen receptor (CAR) T cells. Many next generation antibody therapeutics achieve enhanced potency but often increase the risk of adverse events. Antibody scaffolds capable of exhibiting inducible affinities could reduce the risk of adverse events by enabling a transient suspension of antibody activity. To demonstrate this, we develop conditionally activated, single-module CARs, in which tumor antigen recognition is directly modulated by an FDA-approved small molecule drug. The resulting CAR T cells demonstrate specific cytotoxicity of tumor cells comparable to that of traditional CARs, but the cytotoxicity is reversibly attenuated by the addition of the small molecule. The exogenous control of conditional CAR T cell activity allows continual modulation of therapeutic activity to improve the safety profile of CAR T cells across all disease indications.

Date: 2021
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DOI: 10.1038/s41467-020-20671-6

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